Manufacture of cyclic ketones



Patented Apr. 22, 1941 UNITED STATES PATENT OFFICE 2,239,250 7MANUFACTURE OF CYCLIG KETONEYS Robert Robinson, Oxford, England v NoDrawing. Application April 26, 1939, Serial No. 270,230. In GreatBritain May5, 1938 16 Claims.

This invention relates to the production of cyclic ketones useful, forinstance, as intermediates in chemical synthesis, notably in thesynthesis of medicinal substances.

On condensing ketones of the general formula R.CO.CH3, where R is anaromatic group, for instance a phenyl, naphthyl, or suitably substitutedphenyl or naphthyl group, with iurfuraldehyde, compounds of the generalformula are produced. Thus if the compound R.CO.CH3 is acetophenone theproduct is furfurylidene-acetophenone,

0 i CO.CH=CH.CH/\{CH onion while if R is a p-naphthyl group the productis o CO.CH=OH.C"/\HCH CH-CH The cyclopentenone acetic acids can bereduced (for instance by hydrogenation in methyl alcohol solution in thepresence of palladised strontium carbonate) to compounds in which thefive carbon atom ring is saturated, having the formula COOHA'JH: CO

It has now been found that it ispossible to condense the carboxyl groupof compounds of the types and (where R is a substituted or unsubstitutedphenyl or p-polynuolear-aromatic group, for instance p-naphthyl group)with the group R and form compounds in which the five carbon atom ringis fused to the group R by an intervening six carbon atom ring, byeliminating water between the carboxyl group and the orthoor a-positionof the group R by means of a condensing agent. Thus if the group R is aphenyl group the ring formation will take place at the ortho position togive a compound of skeleton structure while if the group R is afi-naphthyl group, the ring formation will take place at thea-IJOSifiOIl as in the skeleton ring system Where the five carbon atomring of the initial ketone is saturated, the condensation maybeeffectively carried out with the aid of phosphoric anhydride 'in'benzene solution or, preferably, phosphoric anhydride in syrupyphosphoric acid solution, and the product is in general one with askeleton structure of the type H C OOHCH: /C9\ C1 /C&

CH CH2 C( CH CH2 I I I I I CH--- CH: CH CH2 Where, however, the fivecarbon atom ring is unsaturated, the newly formed ring invariablyappears in the enolic form and a product having a skeleton structure ofthe type is obtained. For instance,3,;3-naphthyl-M-cyclopenten-l-one-Z-acetic acid is converted to thecompound 4-hydroXy-3'-keto-1,2-cyclopenteno phenanthrene COOELCHz CO III CCH2 Similarly, 3-phenyl-N-cyclopenten-l-one-2-acetic acid can beconverted to e-hydroXy-3'keto- 1,2-cyclopentenonaphthalene.

The condensation in the case of the compounds I having an unsaturatedfive carbon atom ring can be effected by means of such condensing agentsas sulphuric acid or an aliphatic anhydride, e. g. acetic anhydride orpropionic anhydride. Acetic anhydride (with boiling) is preferablyemployed, and in this case the product appears as the acetyl derivative,the hydroxy group being esterified. This acetyl derivative can readilybe hydrolysed to the hydroxy compound itself, for instance by treatingit with aqueous alcoholic caustic soda and then acidifying.

The group R may as indicated above be suitably substituted, for instanceby one or more hydroxy groups, one or more alkoXy groups such as themethoxy group, or one or more halogen atoms such as chlorine, or bycombinations of such substituents. Thus R may be G-methoxy-p-naphthyl or5-chloro-fi-methoxy-p-naphthyl, in which case the products obtained bymeans of the invention where the five carbon atom ring referred to isunsaturated will be c o cup W0 n2 JL C H:

and

OH YCHz I l t,

respectively, namely (7-methoxy) and (S-chloro- 7-meth0xy) -4- hydroxy-3- keto -l,2- cyclopentenophenanthrenes. The corresponding compoundswhere the five carbon atom ring is saturated are )3 00 on om CHCH2 anewand / E/ Q G0 on on? /OHCH:

CHaO

respectively, namely (3,4-diketo-7-methoxy)- and (3,4 diketo -8- chloro-7- methoxy) 1,2,3,4 tetrahydro 1,2 cyclopentenophenanthrenes. If thegroup R is fi-hydroxy-B-naphthyl, the corresponding hydroxy compoundsare of course obtained.

The invention is illustrated by the following examples (in which'theparts are by weight) Example 1 The compound4-hydroXy-3'-keto-1,2-cyclopentenonaphthalene is prepared as follows:

An intimate mixture of one part of 3- phenyl-A-cyclopenten-1-one-2-acetic acid and 20 parts of concentrated sulphuricacid is heated for 10 minutes at a temperature of C.; 5 parts of waterare then added and heating at the above temperature is continued for 3minutes longer. Water is then added slowly so as to keep the mixture hotfor one or two minutes more. As the dilution with water proceeds therequired product separates: it is collected and washed with aqueoussodium carbonate solution and then with water. It crystallises fromalcohol in pale yellow needles which melt after slight decompositionabove 250 C. at 290-295 C. with decomposition, and which are soluble inaqueous caustic alkali solutions to give solutions with a deep yellowcolour.

The acid employed as a starting material in this example may be preparedas follows:

1 part of -phenyl-vg-diketoheptoicacid (prepared as described by Kehrerand Igler, Ber. (1899), 32, 1178 and (1901), 34, 1263) is dissolved in100 parts of a 2% aqueous solution of potassium hydroxide and the liquidis either boiled for 45 minutes, heated at 95 C. during 1% hours or keptfor 3 days at the room temperature. The solution is then stronglyacidified with hydrochloric acid, and 3-phenyl-A -cyclopenten-l-one-Z-acetic acid is precipitatedin good yield. The acid may berecrystallised from a convenient solvent, such as benzene, .and isobtained as very pale yellow needles which melt at 141 C.

Example 2 The compound 4-hydroxy-3-keto-1,2-cyclopentenophenanthrene isprepared as follows:

parts of the acid 3-p-naphthyl-A -cyclopenten-1-one-2-acetic acid (whichmay be obtained by treating 1 part of -fl-naphthy1-'ydiketoheptoic acidwith 100 parts of a 2% aqueous solution of potassium hydroxide in asimilar way to that described at the end of Example 1) are boiled with'75 parts of acetic anhydride under a reflux condenser during minutesand the excess acetic anhydride is then removed by distillation. Asuitable quantity of methyl alcohol (about parts) is added to theresidue, and the mixture is boiled with trituration of the lumps ofsolid material. After cooling the mixture the crystalline material isfiltered off and dried. It

consists of the acetyl derivative of the required Example 3 The compound7-methoxy-4-hydroxy-3-keto- 1,2cyclopentenophenanthrene is prepared asfollows:

The acid S-(G-methoxy-c-naphthyl) -A -cyclopenten-l-one-Z-acetic acid isconverted into the acetyl derivative of the required product byfollowing the procedure described in Example 2, and this acetyl compoundmelts at 243 C. It may be hydrolysed by boiling with aqueous methylalcoholic potassium hydroxide, when it quickly dissolves, and onacidification of the solution with acetic acid, the required product isprecipitated. It may be recrystallised if desired, by solution inpyridine and by the addition of acetic acid. On heating, the substancedarkens at 268 C., softens at 285 C. and melts to a brown oil at 293-299C.

The acid used as starting material in the example may be prepared asfollows:

A 1% solution of {-(G-methoxy-fl-naphthyl)- r-diketoheptoic acid in 2%aqueous potassium.

acid and it forms straw coloured needles which 75 melt at 204-205 C.

254 5fC'. with decomposition.

25 acid in 20 cc. of. syrupy phosphoric acid of density 7 Example 4 8'-fChlor'o -*7 methoxy-l-hydroxy-li'-keto-1,2- cyclopenteno-phenanthreneis prepared in a similar manner to that described in Examples 2 and 3from 13 (5 chloroxfi-methoxy-p-naphthyl) -A cyclopenten-l-one-Z-aceticacid, which may it- 'se1f;be obtained from{-(5-chloro-6-methoxy-cnaphthyl)ew diketoheptoic acid.

The cyclopentenophenanthrene finally obtained melts at 335 C. withdecomposition, and its acetyl 'deriv tive forms grey leaflets of meltingpoint Example 5 {3 p Naphthylcyclopentan-1-one-2-acetic acid can beobtained by reducing the corresponding A cyclopentenone acid or byreducing the methyl ester of this latter acid and then hydrolysing, thereductionin'either case being carried out with hydrogen the presence ofmethyl alcohol and palladised strontium carbonate.

3,4= Dike-to 1,2,3,l tetrahydro-1,2-cycl;opentenophenanthrene isobtained as follows:

A solution of 6 g. of the above cyclopentanone 1.751s made by gentleheating, and g. of phosphoric'anhydride, is gradually but quickly addedwith vigorous'shaking. The temperature rises above 100 and a faint odourof naphthalene becomes penceptible. A fter'l hour, ice is added to thedark greenmixture and the product is isolated by extraction {with etherand also with ethyl acetate. The solutions are washed with aqueoussodium carbonate, and then with water, dried,

' and evaporated. Theresidue crystallises from a little alcohol to givecolourless needles (M. Pt. 115 C.) :of .the cyclopentenophenanthrene.

3',4 Diketofl-meth'oxy-1,2,3,4-tetrahydro-1,2- cyclopentenophenanthreneis obtained in a similar manner to that described in Example 5 from 5 g.of 3- (S-methoxy-e-naphthyl) -cyclopentan- 1- one-Z-acetic acid(prepared from the A -cyclopentenone acid and preferably from the methylester of this acid) 15 cc. of syrupy phosphoric-acid of density. 1.75and 50 g. phosphoric anhydride. The. product crystallises from alcohol(charcoal) in well shaped prisms of M. Pt. 126-127 C.

It has'been statedabove that the heptoic acid referred to in Example 1may be obtained by the method described in Kehrer and Igler (loc. cit.).Corresponding methods may be employed in the preparation of the heptoicacids referred to in Examples 2, 3 and 4. Thus -5-naphthyl-'diketoheptoic acid may be prepared by adding g. of 2-acetylnaphthaleneand 65 cc. of furfuraldehyde dissolved in 100 cc. of ethyl alcohol to acold solution of 5 g. of sodium in 200 cc. of alcohol. After a fewhours, thecondensation product, namely furfurylidenefl-acetylnaphthalene, has separated in good yield and is sufficientlypure to be used for conversion into the required acid. For this purpose20 g. of the material are mixed with 200 cc. of alcohol and 50 cc. ofhydrochloric acid (of density 1.16) and the whole is boiled under areflux condenser-during 18 hours. The alcohol'is removed by distillation(finally under diminished pressure) and the residue is repeatedlyextracted under a reflux condenser, by means of a boiling mixture ofhydrochloric acid (100 cc. of acid of density 1.16) with glacial aceticacid (100 cc.) and water (200 cc.), the hot aqueous acid solution aftereach extraction being decanted from the oil, filtered and allowed tocool and the crystals separated, The aqueous acid solution is used foranother extraction, and the process is repeated until no furthercrystalline material is obtained when the hot solution is cooled. Thesuccessive crops of crystals are mixed and may be used directly in theprocess described in Example 2, or if required, the product may berecrystallised from acetic acid, when the above naphthyl diketohepto-icacid is obtained as needles which melt at 167169 C.

To prepare 5' (6 methoxy 18 naphthyl) 'ydiketoheptoic acid in a similarmanner, G-acetyl- 2-methoxynaphthalene (obtained for example, by themethod of Haworth and Sheldrick, J. Chem. Soc. 1934, 865), is convertedinto its furfurylidene derivative in the manner indicated above, andthis compound is converted into the required acidby boiling it (14 g.)under a reflux condenser with alcohol (240 cc.) and hydrochloric acid(60 cc. of acid of density 1.16) during 15 hours. After removal of thealcohol by distillation the product is extracted with a boiling mixtureof hydrochloric acid (80 cc. of acid of density 1.16) glacial aceticacid (100 cc.) and water (200 00.), the extraction being repeated as inthe case of the naphthyl derivative until no further appreciable amountof product is obtained. The methoxynaphthyldiketoheptoic acid melts at142443 C. when it is recrystallised from aqueous acetic acid.

It should be added that where the furfurylidene derivative of6acetyl-2-methoxynaphthalene is converted to the diketonic acid byboiling it with hydrochloric acid there is a certain amount ofdemethylation, so that the compound (S-hydroxy-fi-naphthyl)-'y-diketoheptoic acid is produced to some extent, and this on treatmentwith the aqueous potassium hydroxide is converted to3-(6-hydroxy-p-naphthyl)-A -cyclopenten-l-one-2-acetic acid. This lattersubstance on treatment according to Example 3 yields4,7-dihydroxy-3'-keto-l,2 -cyclopentenophenanthrene. Thus in Example 3the mixture of methoxy or hydroxy cyclopentenone acetic acids may betreated, or the crude cyclopentenone acetic acid may be remethylated (e.g. by treatment with methyl sulphate and sodiumhydroxide in aqueous oralcoholic solution) to remove'hydroxy groups in the naphthyl group priorto the final condensation, or the initial crude diketoheptoic acid maybe remethylated. Alternatively, the crude diketoheptoic acid or thepentenone compound may be fully demethylated by heating it with amixture of acetic and hydrobromic acids and a hydroxy-substitutedcyclopentenophenanthrene finally obtained, which if desired may thenitself be methylated.

By employing methods substantially similar to those above described,1-chloro-2-methoxynaphthalene may be successively converted into5-chloro 6 methoxy-2-acetylnaphthalene, the iurfurylidene derivative ofthis ketone and finally into the chloro-methoxynaphthyl-diketoheptoicacid which is referred to in Example 4. Thus1-ch1oro-2-methoxy-6-acetyl-naphthalene (white crystals of melting point124 C.) can be obtained by the action of acetyl chloride on 1-chloro-2-methoxy-naphthalene in nitrobenzene solution in the presence ofaluminium chloride. Its furfurylidene derivative can be obtained andthis converted to the diketo-acid as described above but using two tothree times as much acetic acid. The diketo-acid forms colourlessneedles of melting point l93194 C.

In the claims the terms phenyl radicals havinga hydrogen atom at anortho position, [3-

polynuclear aromatic radicals having a hydrogen atom at the on positionand fi-naphthyl radicals having a' hydrogen atom at the a position areintended .to mean both substituted and unsubstituted phenyl,fl-polynuc1ear aromatic, and pnaphthalene radicals which are attached tothe radical or the radical 7 HOOC.CH2 CO H CH2 R.CCITH2 wherein R is anaromatic radical selected from the group consisting ofphenyl radicalshaving a hydrogen atom at an ortho position, and p-polynuclear aromaticradicals having a hydrogen atom at the on position in the presence of anacid condensing agent toeliminate water between the carboxyl group andthe position of the aromatic radical having the hydrogen atom whereby aclosed ring is formed.

2. A process for the production of cyclic com pounds which comprisesheating a compound of the formula I R.C-( ]H2 wherein R is an aromaticradical selected from the group consisting of phenyl radicals having ahydrogen atom at an ortho position and B- polynuclear' aromatic radicalshaving a hydrogen atom the the a position, in the presence of an -on on,

B-(IJH'. HI and f i Hooocm co H .R.C CH1 wherein. R is an aromaticradical selected from the group consisting of phenyl radicals having ahydrogen atom at'an ortho position and cpolynuclear aromatic radicalshaving a hydrogen atom at the a position, in the presence of an acidcondensing agent selected from the group consisting of acid anhydridesand strong mineral acids to eliminate water between the carboxyl groupand the position of the aromatic radical havingthe hydrogen atom wherebya closed ring is formed. V I

4. A process for the production oi cycliccompounds which comprisesheating a compound of the formula HOOC.GH2 CO I OH;

wherein R is a p-naphthyl radical having a hydrogen atom at the orposition in the presence of an acid condensing agent to eliminate waterbetween the carboxyl group and the position of the naphthyl radica1having the hydrogen atom whereby a closed ring is formed. 7

6. A process for the production of cyclic compounds which comprisesheating a compound of the formula HOOO.C H2, CO

H l R.CCH2

wherein R is an aromatic radical selected from the group consisting ofphenyl radicals having a hydrogen atom at an ortho position andB-polynuclear aromatic radicals having a hydrogen atom at the aposition, in the presence of an acid anhydride to eliminate waterbetween the carboxyl group and the position of the aromatic radicalhaving the hydrogen atom whereby a closed ring is formed.

'7. A process for the production of cyclic compounds which comprisesheating a compound of the formula HOOC.CH2 CO wherein R is an aromaticradical selected from the group consisting of phenyl radicals having ahydrogen atom at an ortho position and fi-polynuclear aromatic radicalshaving a hydrogen atom at the a position, in the presence of analiphatic anhydride to eliminate water between the carboxyl group andthe position of the aromatic radical having the hydrogen atom whereby aclosed ring is formed.

8. A process for the production of cyclic compounds which comprisesheating a compound of" the'f'orm'ula 1 radicalhaving the hydrogen atomwhereby a closed ring is formed.

9. A process for the production of cyclic com-- pounds which comprisesheating a compound of the formula Hoooom oo o T I Rc Von wherein R is ac-naphthyl radical having a hydrogen atom at the at position andcontains at least one substituent alkoxy group, in the presence of anacid condensing agent selected from the group consisting of acidanhydrides and strong mineral acids to eliminate water between thecarboXyl group and the position of the naphthyl radical having thehydrogen atom whereby a closed ring is formed.

10. A process for the production of cyclic compounds which comprisesheating a compound of the formula HO 0 0.0112 /G O t i RC CH2 wherein Ris a p-naphthyl radical having a hydrogen atom at the oc position andcontains at least one substituent halogen atom in the presence of anacid condensing agent selected from the group consisting of acidanhydrides and strong mineral acids to eliminate water between thecarboxyl group and the position of the naphthyl radical having thehydrogen atom whereby a closed ring is formed.

-12. A process for the production of cyclic compounds which comprisesheating a compound of the formula Hoooom Iii-( I wherein R isfi-methoxy-p-naphthyl, in the presence of acetic anhydride to eliminatewater between the carboxyl group and the a position of the naphthylradical whereby a closed ring is formed.

pounds which comprises heating a compound of the formula HOOCIJH:

HOOCLCHa CO wherein R is 6-hydroxy- 8-naphthyl, in the presence ofacetic anhydride to eliminate water between the carboxyl group and the aposition of the naphthyl radical whereby a closed ring is formed.

13. A process for the production of cyclic com- 15. A cyclic compound ofthe formula 0 HI H 0:0 I

wherein X and Y together form part of an aromatic nucleus.

16. A cyclic compound of the formula 0 H i l 20 wherein X and Y togetherform part of an aromatic nucleus.

ROBERT ROBINSON.

